Use of designer GPCRs to study GPCR regulation of key metabolic pathways Armbruster et al. (PNAS 104, 5163-8, 2007) first described a set of muscarinic receptor-based designer GPCRs which are now generally referred to as DREADDs ('designer receptors exclusively activated by designer drugs'). These designer receptors are unable to bind the endogenous muscarinic receptor agonist, acetylcholine, due to two single point mutations introduced into the transmembrane receptor core. Importantly, DREADDs can be efficiently activated by a compound called clozapine-N-oxide (CNO), an agent that is otherwise pharmacologically inert. We are currently in the process of expressing DREADDs with different G protein coupling properties (Gq, Gs, or Gi) in various metabolically relevant cell types. These cell types include adipocytes, pancreatic beta- and alpha-cells, skeletal muscle cells, hepatocytes, and certain neuronal subpopulations of the hypothalamus. Metabolic analysis of these mutant mouse strains has identified several novel pathways that are critical for maintaining blood glucose and energy homeostasis. Skeletal muscle-specific activation of Gq signaling is critical for maintaining euglycemia The inability of skeletal muscle (SKM) to properly respond to insulin plays a key role in the pathogenesis of type 2 diabetes. Studies with transgenic mice expressing a Gq-linked DREADD selectively in SKM cells showed that receptor-mediated activation of SKM Gq signaling promoted glucose uptake into SKM and improved glucose homeostasis in obese, glucose-intolerant mice. These beneficial metabolic effects required the activity of SKM AMPK. On the other hand, obese mutant mice that lacked both Gq and G11selectively in SKM showed severe deficits in glucose homeostasis. GPCR-mediated activation of Gq signaling also stimulated glucose uptake in primary human SKM cells. These novel findings indicate that drugs capable of enhancing SKM Gq signaling may prove useful for the treatment of type 2 diabetes. (Bone DB, et al. Diabetes 68, 1341-1352, 2019) Intra-islet glucagon signaling is required for maintaining normal blood glucose levels Glucagon, a hormone that is released from pancreatic alpha cells, is known to counteract the glucose-lowering effect of insulin, primarily by stimulating glucose release from the liver. In this study, we tested the hypothesis that glucagon can affect the function of adjacent beta cells in a paracrine fashion. To address this question, we generated mice that selectively expressed a Gi DREADD in alpha cells only. CNO treatment of these mutant mice almost completely shut off glucagon secretion in vivo, resulting in impaired insulin secretion, hyperglycemia, and glucose intolerance. We also found indicated that intra-islet glucagon stimulates insulin release primarily by activating beta cell GLP-1 receptors. These new findings strongly suggest that intra-islet glucagon signaling is essential for maintaining proper glucose homeostasis in vivo. (Zhu L, et al. JCI Insight, 2019 Apr 23;5. pii: 127994. doi: 10.1172/jci.insight.127994) DREADD technology reveals the role of Gq signaling in the mouse heart In a collaborative effort with the group of Dr. P. Lipp in Germany, we used DREADD technology to examine the role of Gq signaling in cardiac function. Specifically, we generated transgenic mice line that expressed a Gq DREADD in striated muscle (GqD mice). CNO treatment of the GqD mice resulted in a dose-dependent, rapid mortality due to severe cardiac arrhythmias including lack of P waves, atrioventricular block, and ventricular tachycardia. Individual ventricular and atrial myocytes prepared from GqD mice displayed a positive inotropic response and arrhythmogenic events. Ventricular tissue sections showed strong co-localization of GqD with connexin CX43, and CNO treatment of GqD mice led to PKC-dependent CX43 phosphorylation in cardiac tissue. These findings greatly advance our understanding of the role(s) of Gq signaling in the mouse heart in vivo. (Kaiser E, et al.. Cardiovasc Res 115, 1052-1066, 2019) Beta-arrestin-1 is a component of a beta cell signaling pathway that enhances sulfonylurea-induced insulin secretion Beta-arrestin-1 and -2 (barr1 and barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. To investigate the potential importance of barr1 in regulating beta cell function, we inactivated the barr1 gene in beta cells of adult mice (beta-barr1-KO mice). Beta-barr1-KO mice did not display any obvious phenotypes in a series of in vivo and in vitro metabolic tests. However, glibenclamide and tolbutamide, two widely used antidiabetic drugs of the sulfonylurea (SU) family, showed greatly reduced efficacy in stimulating insulin secretion in the KO mice in vivo and in vitro. Biochemical studies demonstrated that barr1 enhanced SU-stimulated insulin secretion by promoting SU-mediated activation of Epac2. We also showed that barr1 can directly interact with Epac2 and that SUs such as glibenclamide promote barr1/Epac2 complex formation, triggering enhanced Rap1 signaling and insulin secretion. These new data suggest that beta cell barr1 represents a potential target for the development of novel antidiabetic drugs. (Barella LF,et al.. J Clin Invest 130. pii: 126309. doi: 10.1172/JCI126309, 2019) Receptor-mediated activation of Gs signaling in adipocytes causes pronounced metabolic improvements in mice Adipocytes play a central role in the regulation of whole-body glucose and energy homeostasis. To examine the metabolic effects of acute and chronic activation of Gs signaling selectively in adipocytes, we generated a novel mutant mouse strain (adipo-GsD mice) that expressed a Gs DREADD (GsD) selectively in adipocytes. The adipo-GsD mice were maintained on either regular chow or a high-fat diet and then subjected to a comprehensive series of metabolic tests. CNO treatment of the adipo-GsD mice caused striking improvements in glucose homeostasis and protected mice against the metabolic deficits caused by an obesogenic diet. Chronic CNO treatment of adipo-GsD mice caused pronounced increases in energy expenditure and reduced food intake, resulting in a decrease in body weight and fat mass when mice consumed a calorie-rich diet. These findings are of high relevance for the development of novel antidiabetic and anti-obesity drugs. (Wang L, et al.. Mol Met pii: S2212-8778(19)30457-0. doi: 10.1016/j.molmet.2019.06.018. Epub ahead of print, June 2019) Beta-arrestin-2 expressed by adipocytes is required for maintaining normal blood glucose levels and body weight To investigate the potential importance role of beta-arrestin-2 (barr2) in regulating adipocyte function, we generated mice that selectively lacked barr2 in adipocytes. These mutant mice showed significantly reduced adiposity and striking metabolic improvements when consuming an obesogenic diet. We found that these beneficial metabolic effects were caused by enhanced signaling through adipocyte beta-3 adrenergic receptors (b3-AR), indicating that barr2 represents a potent negative regulator of adipocyte b3-AR activity in vivo. The beneficial metabolic effects caused by adipocyte barr2 deficiency were absent in adipocyte barr2-PRDM16 double KO mice, indicating that the metabolic improvements caused by adipocytes barr2 deficiency are mediated by the browning/beiging of white adipose tissue. These novel findings suggest that 'G protein-biased' b3-AR agonists may prove useful for the treatment of obesity and related metabolic disorders. (Pydi SP, et a. Nat Commun 10:2936, https://doi.org/10.1038/s41467-019-11003-4, 2019)